Laurence Gauzy

Synthesis of optically active β,γ-alkynylglycine derivatives☆

Abstract Full results on the first synthesis of optically active β,γ-alkynylglycine derivatives from naturally occurring L-serine are described. The methodology uses L-serinal as a key intermediate and allows great versatility in the introduction of N-protective groups and of alkyne substitution. The N-Boc protected β,γ-alkynylglycine derivatives described have ee greater than 90%.

En route to optically active ethynylglycine derivatives

Abstract First results in the synthesis of chiral non racemic ethynylglycine derivatives from protected L-serinal are described.

Synthesis of azepane scaffolds on solid support for combinatorial chemistry

Abstract Enantiopure C 2 -symmetric azepanes have been synthesized on solid support as scaffolds for the synthesis of peptidomimetics in combinatorial chemistry. The key step involves Rink resin as a formal equivalent of ammonia in the nucleophilic opening of L-iditol bis-epoxide.

Synthesis of C2-symmetric bis(cyclic isothioureas) as potent inhibitors of glycosidases

Abstract Enantiopure C 2 -symmetric bis (cyclic isothioureas), considered as potent inhibitors of glycosidases, have been synthesized from D-mannitol. The key step involved a mercuric-catalyzed transformation of a cyclic 1,3-thiazolidine-2-thione into a 2- N-tert -butylamino-1,3-thiazoline.

Abstract LB-053: Towards new cryptophycins as promising payloads for ADC

Cryptophycins are a class of macrocyclic depsipeptides produced as secondary metabolites by cyanobacteria of the genus Nostoc and were found to bind to microtubules at the vinca site. The natural product C-1 isolated in 1990 and the synthetic derivative C-52 displayed potent in vitro and in vivo antitumor activity in preclinical models. Cryptophycin C-52 (LY355703) produced marginal antitumor activity at MTD in two phase II lung cancer trials and was therefore discontinued. Considering its higher potency versus other tubulin binders such as maytansine and auristatin, this chemical series was selected for an ADC approach. Several conjugates were evaluated in vitro and in vivo based on the conjugation of C52 derivatized at the para-benzylic position of the macrocycle. As described in this study, this optimization led to the discovery of cryptophycin ADC which displayed potent antitumor activity in vivo. However, these conjugates were found unstable in mice plasma while being stable in the plasma of non-rodent species. This species-dependent instability was shown to be the result of a mice plasmatic metabolization of C52 macrocycle once conjugated to the antibody. We therefore designed and synthesized new cryptophycin ADC which exhibited improved plasmatic stability when tested in mice and enhanced therapeutic index in comparison with C52 ADC. In conclusion, these data demonstrated the potent in vitro and in vivo antitumor activity of these new cryptophycin ADC and warrant further development of this cytotoxic payload for an ADC approach. Citation Format: Marie-Priscille Brun, Herve Bouchard, Francois Clerc, Jidong Zhang, Pierre-Yves Abecassis, Celine Amara, Eric Beys, Florence Efremenko, Celine Nicolazzi, Marie-Helene Pascual, Olivier Pasquier, Alain Krick, Pierre-Francois Berne, Laurence Gauzy, Nathalie Karst, Sylvain Huille, Christophe Henry, Anne-Marie Lefebvre, Ingrid Sassoon. Towards new cryptophycins as promising payloads for ADC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-053.